Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia

Abstract

We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity.

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

“…8,16 Two recent studies have also shown that flavopiridol can induce partial remission in fludarabine-resistant and del17p13 patients with an average of four prior therapies. 17,18 However, these current treatments are still far from satisfactory, with o50% response rates recently reported from ongoing clinical trials. Additionally, given the early relapse of these patients, there is an urgent need for the identification of new, more potent alternatives.…”

Refractory chronic lymphocytic leukemia - new therapeutic strategies

“…30 patients suffered acute tumor lysis syndrome, one patient died of it. Most frequent adverse events were neutropenia, diarrhea and cytokine-release syndrome [30]. 121 patients were treated according to the protocol and received infection prophylaxis against HSV/VZV and pneumocystis jirovecii.…”

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

“…By changing the dosing schedule from 72hr infusion to 30 minutes i.v. bolus followed by 4-hr-infusion a significant difference in the clinical outcome and final response of refractory CLL patients was achieved [159].…”